There is a urgent need to develop more and better vaccines to combat both natural pathogens (e.g., AIDS, SARS) and pathogens that may be used by bioterrorists (e.g., anthrax). This application will test the hypothesis that activation of purinergic receptors (i.e. the cell surface receptors that respond to purines and related agonists), which are expressed on the surface of antigen presenting cells in the skin, can enhance the effectiveness of vaccines, thereby defining a new class of adjuvants. This hypothesis is based on evidence that purinergic receptors are expressed on antigen presenting cells in the skin (i.e., Langerhans cells) and that purines and agonists that act on purinergic receptors enhance antigen presentation in vitro. If this hypothesis is correct, then agents that activate purinergic receptors may serve as potent adjuvants to enhance the efficiency of vaccines. We will take two distinct approaches to test each of three aims. Specifically, we propose: (1) to determine if agents that act on purine receptors augment cell-mediated immunity in vivo; (2) to determine if agents that act on purine receptors enhance humoral immunity in vivo; and (3) to determine if agents that act on purine receptors enhance the ability of vaccination to provide protective immunity against challenge with tumors, infectious agents or toxins in well-defined animal models. Although this proposal is relatively risky, there may be broadly applicable and substantial benefits benefits: (1) More effective and, possibly safer, vaccination protocols may be developed. (2) Some molecules that are currently not suitable for vaccinations may gain effectiveness opening the way for the development of novel vaccines. (3) It may be possible to develop new therapeutic vaccines for infectious agents and malignancies. (4) This work may provide in vivo data to support the existence of a new class of adjuvants, and understanding their mechanism of action should provide insight into the regulation of the immune system. (5) This work may provide insights into the physiological processes that modulate the immune response and further our understanding of the mechanisms of established adjuvants.